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Culprit or Bystander ? The Role of the Fallopian Tube in “Ovarian” High-Grade Serous Carcinoma Elizabeth M. Swisher 1 , Rochelle L. Garcia 2 , Mark R. Kilgore 2 , and Barbara M. Norquist 1

“Ovarian” (pelvic) carcinomas comprise a heterogeneous

group of neoplasms, which may be unique among solid

tumors in the lack of consensus about the organ or origin.

Traditionally, nonuterine pelvic carcinomas have been labeled

as ovarian, fallopian tube (FT), or primary peritoneal based on

arbitrary assignations based on the volume of disease identi-

fi ed at different sites and the presumption that the ovary is

the most common site of origin. For example, Gynecologic

Oncology Group (GOG) criteria specify the ovary as the pri-

mary site of disease for any nonuterine high-grade serous car-

cinoma (HGSC) involving multiple intra-abdominal organs

with at least 0.5 cm of ovarian stromal involvement. Similarly,

if both the ovary and FT have bulky neoplasm, the primary

site is labeled ovary unless there is a clear transition from

intraepithelial neoplasm to invasive carcinoma in the FT.

However, no such transition is required to label nonuterine

HGSC as ovarian primary, and a similar precursor intraepi-

thelial neoplasm of the ovary has yet to be identifi ed. The

increased use of neoadjuvant chemotherapy, which affects

disease distribution, further increases the diffi culty of deter-

mining the site of origin. Understanding the origin and the

path of progression of these aggressive carcinomas directly

bears on strategies for risk assessment, early detection, and

prevention.

The ovary is primarily composed of stroma with a smaller

fraction consisting of germ cells and ovarian surface epithe-

lium, which is derived from primordial mesothelium. Pelvic

nonuterine carcinomas can be broken down into a number of

distinct histologic subtypes, including serous, clear cell, endo-

metrioid, mucinous, and those with mixed features. Each of

these subtypes is associated with distinct molecular pathways

and may arise from different organs and cells of origin. For

example, clear cell and endometrioid carcinomas probably

arise in endometriosis and share characteristic alterations in

1 Division of Gynecologic Oncology, Department of Obstetrics and Gyne-cology, University of Washington, Seattle, Washington . 2 Department of Pathology, University of Washington, Seattle, Washington.

Corresponding Author: Elizabeth M. Swisher , University of Washington, 1959 NE Pacifi c Street, Seattle, WA 98195. Phone: 206-543-3669; Fax: 206-543-8315; E-mail: swishere@uw.edu

doi: 10.1158/2159-8290.CD-16-1197

©2016 American Association for Cancer Research.

Summary: The concurrence of intraepithelial high-grade neoplasia in the fallopian tube with metastatic implants

has been taken as evidence of a tubal origin for high-grade serous pelvic carcinomas. In the current issue, Eckert

and colleagues perform detailed genomic phylogenetic analyses and demonstrate that some cases of high-grade

serous intraepithelial tubal neoplasia are metastatic implants and not precursor lesions. Cancer Discov; 6(12);

1309–11. ©2016 AACR.

See related article by Eckert and colleagues, p. 1342 (7).

PTEN, PIK3CA , and ARID1A . Serous carcinomas are divided

into low-grade and high-grade carcinomas. HGSC is the most

common form of nonuterine pelvic carcinoma, representing

approximately 70% of cases, and is characterized by near-

universal mutations in TP53 , genomic instability, and defects

in DNA repair, particularly homologous recombination repair.

Pelvic HGSC usually presents with metastatic and bulky multi-

focal disease, making the organ of origin diffi cult to determine.

It was recognized in the early 1980s that HGSC could be

multifocal and coexist with intraepithelial neoplasia in the

FT, and Bannatyne and Russell recommended more careful

pathologic evaluation of the entire FT in cases with HGSC

( 1 ). But it was the uptake of preventive surgeries in the late

1990s for genetic risk of “ovarian” carcinoma conferred by

inherited mutations in BRCA1 and BRCA2 ( BRCA1/2 ) that

provided a new window into the origin of HGSC ( 2, 3 ). Occult

neoplasms identifi ed at risk-reducing surgery in BRCA1/2

mutation carriers are almost always located in the FT and

not the ovary, including both microscopic invasive HGSC

and high-grade intraepithelial neoplasia [also termed serous

tubal intraepithelial carcinoma (STIC)]. The predominance

of the FT as the site of these early neoplasms led to the tubal

hypothesis: that the FT is the origin of nonuterine pelvic

HGSC. The practice of complete serial sectioning of the FTs

became standard of care for risk-reducing surgeries in high-

risk women, a practice essential to the identifi cation of micro-

scopic neoplasia in the FT ( 2, 3 ). The tubal origin of HGSC

was further supported by a series of studies that identifi ed

frequent occult tubal involvement in advanced-stage pelvic

HGSC if careful serial sectioning of the FT was performed ( 4 ).

However, these studies showed an association between neo-

plastic lesions in the FT and elsewhere, without proving the

site of origin. The relative role of the FT in sporadic HGSC

may also have been confused by not distinguishing sporadic

from inherited pelvic HGSC in most studies.

Nevertheless, the paradigm shift toward a tubal origin of

nonuterine HGSC was so complete that the tubal hypothesis

was featured by Dr. Oz in 2009 and discussed widely on blogs.

High-risk women wondered why they needed to remove their

ovaries and suffer the consequences of surgical menopause if

the real culprit was the FT. The clinical implications are great;

risk-reducing salpingo-oophorectomy reduces mortality of

BRCA1/2 mutation carriers ( 5 ). The safety for high-risk women

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of retaining the ovaries is unknown, and a randomized trial

comparing bilateral salpingectomy to salpingo-oophorectomy

would be unethical. For women at normal risk of “ovarian”

cancer, some experts have suggested that bilateral salpingec-

tomy should be the preferred method of female sterilization

and should be performed with every hysterectomy when ova-

ries are retained (called opportunistic salpingectomy; ref. 6 ).

The study by Eckert and colleagues provides new insights

into this thorny problem ( 7 ). The diminutive size of STIC

lesions in the FT provides challenges for detailed molecular

characterization. Nevertheless, the authors isolated neoplastic

cells using laser-capture microdissection and applied whole-

exome sequencing to STIC paired with metastatic deposits

from the same patient. They then used phylogenetic analyses

to postulate the primary site. Among eight women with STIC

and multifocal HGSC, mutational profi ling identifi ed the

STIC as the precursor lesion in half. But notably, in at least

two cases, the STIC appeared to be a metastatic implant.

They experimentally supported the plausibility of intramu-

cosal spread to the FT by demonstrating that HGSC sphe-

roids can implant into the epithelium of e x vivo FT explants

and attain a similar appearance to STIC (Fig. 4E of ref. 7 ).

The potential for intramucosal metastatic implants is not

unique to this scenario, as it is a well-documented fi nding in

bronchial epithelium from lung carcinomas and even in FT

epithelium from nongynecologic sources ( 8, 9 ). Previous evi-

dence for the possibility of metastatic spread to the FT from

HGSC came from the observation of multifocal STIC present

in some advanced HGSC cases and the presence of STIC in

some cases of uterine serous carcinomas.

These fi ndings call into question previous assumptions

that the fi nding of synchronous STIC and metastatic HGSC

implicates the FT as the organ of origin. The best evidence

for a FT origin for HGSC remains the location of the early

microscopic cancers identifi ed in women with increased gen-

etic risk. When only microscopic cancer is identifi ed, FTs are

serially sectioned, and cases with multifocal disease or elevated

serum CA125 (implying macroscopic disease) are excluded,

the FT is the location in 90% of HGSC in BRCA1/2 mutation

carriers. The role of the FT in sporadic HGSC is less well

defi ned. Eckert and colleagues evaluated only cases without

BRCA1/2 mutations and provide some answers. In half of

the cases, STIC was the presumed precursor lesion, so the FT

remains the likely origin for many sporadic “ovarian” HGSCs.

But these cases were specifi cally chosen because they had

identifi able STIC, and many women with sporadic ovarian

and peritoneal HGSC have no such identifi able lesions. There-

fore, the fraction of unselected sporadic HGSCs that have an

FT origin remains unknown. Larger phylogenetic studies of

HGSC genotyped for inherited risk are needed to answer this

question. These data will be critical in understanding the effi -

cacy of opportunistic salpingectomy in reducing cancer risk.

The origin of HGSC that is labeled primary peritoneal

carcinoma is another interesting mystery on which the work

by Eckert and colleagues sheds light and raises important

questions. In BRCA1/2 mutation carriers who have undergone

bilateral salpingo-oophorectomy, the majority of primary per-

itoneal carcinomas occur in the fi rst 5 years after risk-reducing

surgery with only rare cases reported after that ( 10 ). These

data suggest that an occult FT or ovarian carcinoma missed at

Figure 1.   Spread patterns of HGSC (blue deposits). In some cases of sporadic pelvic HGSC, the high-grade intraepithelial neoplasia (also called STIC) is the precursor lesion, spreading to the ovary and omentum in parallel or sequentially. In other cases, HGSC from other sites spreads to the FT as a metastatic intraepithelial lesion histologically indistinguishable from intraepithelial neoplasia originating in the FT .

Fallopiantube

Bladder

Intraepithelialneoplasia

Smallintestine

Colon

PeritoneumUterus

Cancer

Ovary

Omentum

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time of risk-reducing surgery might be the actual source of the

majority of “primary peritoneal” carcinomas in women with

BRCA1/2 mutations. The omentum is typically the anatomic

site of bulkiest tumor in “primary peritoneal” carcinoma. In

the two cases in which the STIC was secondary to metastatic

spread, Eckert and colleagues identifi ed the omentum as the

most “basal” of the sampled tumor sites ( 7 ). In women with-

out cancer, the omentum is a common site of endosalpingi-

osis, non-neoplastic FT-like epithelium occurring outside the

FT. Possibly, endosalpingiosis in the omentum was the site

of origin, though endosalpingiosis is more often associated

with low-grade serous neoplasms. Alternatively, the primary

site may not have been sampled for these 2 patients, and the

omentum represented an early site of metastasis with further

metastasis occurring from the omentum to FT mucosa.

Understanding the origin of pelvic carcinomas is critically

important for optimizing cancer prevention strategies at both

the individual and population levels. In studying the origin of

HGSC, it remains important to separate cases driven by germline

mutations in BRCA1/2 or other ovarian cancer susceptibility

genes from sporadic carcinomas. Eckert and colleagues have

made a seminal contribution to our understanding by providing

genomic and experimental data supporting the ability of at least

some sporadic HGSC to secondarily implant into the FT mucosa

( Fig. 1 ). We congratulate the authors and look forward to further

revelations on the molecular progression of pelvic HGSC.

Disclosure of Potential Confl icts of Interest No potential confl icts of interest were disclosed .

Grant Support B.M. Norquist is supported by a Liz Tilberis Career Development

Award from the Ovarian Cancer Research Fund Alliance.

Published online December 5, 2016.

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2016;6:1309-1311. Cancer Discov   Elizabeth M. Swisher, Rochelle L. Garcia, Mark R. Kilgore, et al.   High-Grade Serous CarcinomaCulprit or Bystander? The Role of the Fallopian Tube in ''Ovarian''

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